Glioblastoma multiforme (GBM) is the most common and highly aggressive primary brain tumor, representing approximately 50% of all brain tumors. With standard of care therapy, which currently includes surgery, radiation, and temozolomide chemotherapy, patient prognosis is poor with an average survival of 12-15 months. Despite a clear and urgent need to improve treatment options for patients, most therapies aimed at directly targeting glioma cells in GBM have failed, largely due to substantial genetic and tumor cell heterogeneity, and a high propensity for recurrence.
As an alternative to tumor-targeted therapy, targeting the tumor microenvironment (TME) has been shown to be an effective therapeutic strategy in several tumor types, including brain tumors. Brain-resident and bone marrow-derived tumor-associated macrophages (TAMs) are the predominant immune cell population in GBMs comprising up to 30% of the bulk tumor mass. In many types of cancer, including glioma, high TAM numbers are associated with high grade tumors and poor patient prognosis.
Macrophages depend on colony stimulating factor (CSF)-1 for their differentiation and survival, and thus strategies to target macrophages often include blockade of the CSF-1 receptor (CSF-1R). It was previously shown that blocking CSF-1R with the compound BLZ945 in advanced, high-grade, gliomas resulted in rapid tumor de-bulking by more than 30% after just 7 days of treatment (Pyonteck et al., “CSF-1R inhibition alters macrophage polarization and blocks glioma progression;” Nat. Med. 2013 October; 19(10): pp. 1264-72). However, prior to the present invention the efficacy of CSF-1R inhibitors such as BLZ945 in longer-term treatment of high-grade glioma was unknown. Similarly, prior to the present invention it was not known whether longer-term treatment of GBM with CSF-1R inhibitors, such as BLZ945, might result in the emergence of drug resistance, and if so, what strategies might be available to ameliorate such drug resistance.